Nitroxyl (HNO) as a vasoprotective signalling molecule

B.K. Kemp-Harper, Biomedicine Discovery Institute, Department of Pharmacology, Monash University, Clayton, VIC 3800, Australia.

Nitroxyl (HNO), the reduced and protonated congener of nitric oxide (NO·), is rapidly emerging as a novel entity with distinct pharmacology and therapeutic advantages over NO· (Bullen et al. 2011). Unlike NO•, HNO interacts directly with thiols to increase myocardial contractility, elevates plasma levels of calcitonin gene-related peptide and is resistant to scavenging by superoxide (^.O₂⁻). Whilst these unique properties of HNO confer potential in the treatment of heart failure, our studies have also highlighted vasoprotective actions of HNO. The vasoprotective actions of HNO were studied in models of hypertension and atherosclerosis. Our studies have shown that like NO·, HNO donors serve as potent vasorelaxants (including human arteries; Andrews et al., 2015), and inhibit platelet aggregation, mediating these effects predominantly via sGC activation and an elevation in cGMP. In contrast to NO·, HNO donors are resistant to scavenging by ^.O₂⁻ and vascular tolerance development and target distinct vascular signaling pathways. Indeed we have shown that the vasoprotective (vasorelaxant, anti-aggregatory) actions of HNO are sustained in the setting of hypertension (SHR rat) and atherosclerosis (ApoE-/- mouse), where endogenous NO· bioavailability is reduced. Furthermore, HNO rapidly suppresses vascular ^.O₂⁻ generation from Nox2-NADPH oxidase, via a cGMP-independent action, and limits vascular dysfunction (Miller et al., 2013). In conclusion, HNO donors offer considerable advantages over traditional NO· donors due to their preserved bioavailability in oxidative stress, lack of tolerance and favourable vasoprotective properties and may provide innovative pharmacotherapy for the treatment of vascular disease.

Andrews KL, Lumsden NG, Farry J, Jefferis AM, Kemp-Harper BK, Chin-Dusting JP (2015). Matrix metalloproteinase-9 inhibition ameliorates pathogenesis and improves skeletal muscle regeneration in muscular dystrophy. Clin Sci 129, 179-187.

Bullen ML, Miller AA, Andrews KL, Irvine JC, Ritchie RH, Sobey CG, Kemp-Harper BK (2011). Nitroxyl (HNO) as a vasoprotective signaling molecule. Antioxid Redox Signal 14, 1675-86.

Miller AA, Maxwell KF, Chrissobolis S, Bullen ML, Ku JM, Michael De Silva T, Selemidis S, Hooker EU, Drummond GR, Sobey CG, Kemp-Harper BK (2013) Nitroxyl (HNO) suppresses vascular Nox2 oxidase activity. Free Rad Biol Med 60, 264-271